Method for producing salts of tolperisone

ABSTRACT

The invention relates to a method for producing an acid addition salt of 2,4′-dimethyl-3-piperidino-propiophenone (tolperisone) with a pharmaceutically acceptable acid, of the formula (I). 
     
       
         
         
             
             
         
       
     
     According to the invention, 4-methylpropiophenone is reacted with piperidine hydrochloride and 1,2-dioxolane in the presence of an acid serving as a catalyst, and the tolperisone obtained in the form of an acid addition salt is separated by filtering after the reaction mixture has cooled down.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 10/537,434, filed Jul. 15, 2005, which is a 371national stage application of International Application no.PCT/AT03/00092, filed Mar. 31, 2003, which claims priority to AustrianPatent Application No. A 1823/2002, filed Dec. 5, 2002, from whichapplications priority is claimed pursuant to 35 U.S.C. §§ 119 and 120,which applications are hereby incorporated by reference in theirentireties.

The invention relates to a method for manufacturing organic andinorganic acid addition salts and hydrates of tolperisone having thegeneral formula B:

Tolperisone is the international name for a muscle relaxant having thechemical name (RS)-2,4′-Dimethyl-3-piperidinopropiophenone and alsohaving the molecular formula C₁₆H₂₃NO. Tolperisone is a muscle-relaxingpharmaceutical, with the following formula A

The main indications for tolperisone are illnesses which are accompaniedby painful muscle spams, e.g. spinal column syndromes, muscular painwith degenerative illnesses, sports and occupational repetitive motionsyndromes and the Fibromyalgia syndrome.

An advantage of the treatment with tolperisone is the fact thatfunctional parameters e.g. the mobility of the patient, is alsoimproved. Patients having long-term administration of tolperisone have agood therapeutic relationship and the confidence basis necessary fortherapeutic success by the absence of central side effects usuallyassociated with the further employment of this medicine.

Tolperisone and its salts with the general formulas A and B arewell-known and can be manufactured by different chemical pathways. Thewell-known methods in the synthetic art have the disadvantage that theyutilize raw materials that are not commercially available, and also havethe drawbacks of complicated reaction conditions on an industrial scalewhich lead to low yields.

J. Labelled Cpd. Radiopharm 42, 1125-1134 (1999)

In order to be able to manufacture radioactively labeled tolperisone,Ditriech provides a direct synthesis pathway on the basis of4′-methylacetophenone and paraformaldehyde. The multi-level synthesisleads to a mixture of substances and the tolperisone can only beisolated by column chromatography.

Jap. Pat. 04005283 A2 19920109

Disadvantages of this method are the multi-level synthesis, theintermediate product must be isolated and purified.

Jap. Pat. 54032480 19790309

The production of the halogen derivative is complex and expensive.

Jap. Pat. 54036274 19790316

This synthesis pathway starts from expensive raw materials and itdevelops several by-products (ie., dibromopentane).

Jap. Pat. 54030178 19790306

The raw material needed for this synthetic pathway must be manufacturedover several stages. Furthermore, the reaction must be worked underexclusion of humidity to avoid the hydrolysis of aluminum trichloride.

Jap. Pat. 54027571 19790301

This synthesis pathway starts from expensive raw materials and itdevelops several by-products (e.g. vinyl compounds).

Chem. Pharm. Bull. 42, 1676 (1994):

Kazuharu et al. describe in Chem. Pharm. Bulletin 42(8) 1676 (1994) theproduction of tolperisone by the Mannich reaction. The published yieldsare relatively high, however several by-products are removed by aqueousextraction. The multi-level processing is unfavorable and expensive,since the substance is isolated first in oily form and only afterwardsas the hydrochloride.

RO 75-83082 19750804 (CAN 98: 125629)

The use of formaldehyde that is not in protected form has severaldisadvantages, like water in the reaction mixture, high toxicity(IHL-TCLO HMN 17 mg/m³/30 m; ORL-RAT LD₅₀ 100 mg kg⁻¹) or formation ofvery difficultly soluble paraformaldehyde.

Jap. Pat. 20,390 (1965)

Matatsugu et al. published a method for the production of tolperisone onthe basis of paraformaldehyde in a mixture ofnitromethane:ethanol:toluene (40:5, 5:11) using aqueous hydrochloricacid. The indicated reaction results in a conglomerate and working withnitromethane is expensive due to its danger.

Hung. Pat. 144,997 (1956)

Nádor et al. describes an industrial method for the production oftolperisone using ethanol saturated with gaseous formaldehyde. Thismethod leads to tolperisone hydrochloride, the yields however are lowand working with gaseous formaldehyde is expensive due to its danger.

Among the unwanted isomers which are notable in particular are:

-   (C): 2-Methyl-1-(3-methylphenyl)-3-piperidin-1-ylpropan-1-one;-   (D): 2-Methyl-1-(2-methyl phenyl)-3-piperidin-1-ylpropan-1-one;

On the basis of the synthesis method and the quality (purity) of theassigned basic materials the following impurities in the final product(tolperisone) are possible:

Component Chemical name Chemical Structure Piperidine HCl Piperidinehydrochloride

C2-methyl-1-(3-methylphenyl)-3-(1-piperidinyl)-propanonehydrochloride3-tolperisonehydrochloride

4-MMP 1-(4-methylphenyl)-propanone4-methylpropiophenone

E 2-methyl-1-(4-methylphenyl)-propenone

D2-methyl-1-(2-methylphenyl)-3-(1-piperidinyl)-propanonehydrochloride2-tolperisonehydrochloride

The objective of the invention is to develop an improved method formanufacturing tolperisone with improved purity and its salts, feasiblein a technical scale, without the disadvantages that arise from thewell-known synthetic pathways.

The objective is accomplished with a method, which exhibits thecharacteristics of patent claim 1.

Favourable synthetic arrangements according to the methods of theinvention are the subject of the claims.

With the below described analytical methods these impurities can beascertained to be near 0.1%.

The analysis methods are described below.

1.1. Method 1: Analysis of the Content of Tolperisone and Impurities3-tolperisone (C), 4 methylpropiophenone (4-mpp) and Vinylketone (E):

The determination of the content of tolperisone and the impuritiesmentioned above takes place by means of measurements against externalstandards on a HPLC system with UV detection. The stationary phaseconsists of a functionalized polysaccharide. As mobile phase a binarysystem of a borate buffer and an organic modifier (acetonitrile) isused.

1.2. Method 2: Analysis of the Content 2-Tolperisone (D):

For the determination of the content of 2-tolperisone a HPLC systemalong with UV detection is likewise used. The stationary phase is acalixarene bound on silicate. As mobile phase a mixture of phosphatebuffer and methanol is used.

1.3. Method 3: Analysis of the Content of Piperidine Hydrochloride:

For the regulation of piperidine HCl a quantitative LC/MS method isused. The stationary phase consists of octadecysilyl derivatized silicagel. The binary mobile phase contains tri-chloro acetic acid andmethanol.

With the described methods also the levels of C and D can be ascertained(determined), although these position isomers hardly differ in theirchemical characteristics from tolperisone and therefore are separatedwith difficulty.

So far for determining the content of tolperisone a regular titrimetricmethod was used (Pharm. Jap. XI), with which only the sum of the levelsB, C and D can be determined.

With the new HPLC method for determining tolperisone, 2-tolperisone,3-tolperisone and the remaining impurities and the LC/MS method fordetermining piperidine hydrochloride, the problems of the well-knownanalyses are eliminated.

With these analysis methods, the purity was determined according to theinvention for the tolperisone made according to the invention and fortolperisone preparations available in the marketplace.

The results are summarized in the following table:

Product description 2-Tolperisone 3-Tolperisone Piperidine Vinyl Ketone4-MPP Mydeton 50 mg 0.3% 0.8% <0.05% <0.05% <0.05% Tablets from GedeonRichter Mydeton 510 mg 0.6% 1.2% <0.05% <0.05% <0.05% Tablets fromGedeon Richter Mydocalm 50 mg 0.6% 1.1% <0.05% <0.05% <0.05% TabletsFrom Strathmann Toperisone of the <0.05%    0.1% <0.05% <0.05% <0.05%present invention

The analyses summarized in the table show the fact that tolperisone isclearly worse in products present in the market in its purity profile,particularly in the content of position isomers, than the tolperisoneavailable in accordance with the invention and thus does not correspondto the current guidelines of the European regulatory agencies.

The method according to invention for the synthesis of tolperisone canbe shown as follows:

As the starting materials 4-methylpropiophenone, piperidinehydrochloride and 1,2-dioxolane are used as reaction partners and thelatter is used preferentially also as solvent.

Using 1,2-dioxolane in place of formaldehyde and the high yield achievedafter the direct isolation of tolperisone makes the single-step reactioneconomical also on an industrial scale.

With the method according to the invention it is feasible that thestarting 4-methylpropiophenone may be contaminated with up to 5%3-methylpropiophenone and up to 2% 2-methylpropiophenone, and with themethods according to the invention nevertheless the necessary finalproduct purity is attained.

With the method according to the invention for manufacturing salts oftolperisone of the formula B aqueous hydrochloric acid can be used incatalytic quantities for the aminomethylation reaction accomplished in1,2-dioxolane. Thus the final product of the salts of tolperisone can beseparated easily by the addition of ethyl acetate and tert-butylmethylether in accordance with general formula B for example as chloride(X═Cl) and can be separated from the reaction mixture by precipitation.

The separated salt of tolperisone possesses already high purity and afavorable impurity profile, however if necessary it can be furtherpurified e.g. by further recrystallization.

Altogether the method of the invention is suitable also for carrying outon an industrial scale, since a purification step represents a smallexpenditure by means of salt precipitation only. The method of theinvention can be implemented and also automated.

The method of the invention permits manufacturing of suitable salts oftolperisone with acids by addition of the pharmaceutical active, topreferential acids such as mineral acids, and more in particularhydrochloric acid.

Favourable method and variants thereof according to the invention aredescribed on the basis the following examples:

EXAMPLE 1 Production of Tolperisone Hydrochloride

In a 3-L-three neck flask with a reflux condenser, a calcium chloridedrying tower, and under an argon flow, 200 ml of 1,3-dioxolane and 146.2ml of 4-methylpropiophenone are subjected to agitation and then there isadded through a funnel 100 g piperidine hydrochloride and 4.0 ml of 33%aqueous hydrochloric acid. The powder in the funnel is washed afterwardswith 20 ml 1,3-dioxolane, and the stirrer is switched on in the reactionflask. The reaction mixture is purged once with argon and stirred at100-105° C. bath temperature (83-86° C. interior temperature). The whiteprecipitate dissolves after approximately 15-16 hours. After 18-20 hoursthe thin layer chromatogram shows no more piperidine. After 24 hours theheating is switched off and the oil bath is removed and while stillwarm, and under vigorous stirring to the clear reaction solution, thereis added 800 ml ethyl acetate and then the solution is cooled to ambienttemperature and then further treated with 400 ml methyl tert-butylether(MTBE). The resulting precipitate is agitated at 0 to 10° C. for anadditional 2 hours, and then filtered off over a glass filter (Po-3) andwashed afterwards twice with 200 ml MTBE each time. The substance isdried in the vacuum drying oven at 75-80° C. and 20-40 mbar for 16 to 24hours.

Yield: 206.5 g (89.1%, computed on piperidine hydrochloride) colorlesspowder

mp.: 169° C.

Analysis:

Melting point 2-Tolperisone 3-Tolperisone 4-Tolperisone Piperidine OtherImpurities 4-MPP 169° C. 0.22% 0.30% 98.0% <0.05% <0.05% <0.05%

EXAMPLE 2 Purification of Tolperisone Hydrochloride

Into a 500 ml-three-necked flask with stirrer, reflux condenser anddropping funnel 58.0 g tolperisone are added and mixed with 87 ml ofisopropyl alcohol. The reaction mixture is heated up to the boilingpoint, whereby a clear solution develops. The warm reaction solution ismixed with 261 ml MTBE and cooled under constant stirring to ambienttemperature. The resulting suspension is cooled under stirringconditions at ambient temperature for 14-18 hours, then further cooledto 5-10° C. and after 2-3 hours of stirring it is filtered off. Theprecipitate is washed afterwards twice with 80 ml MTBE each and dried inthe vacuum oven at 55-60° C. and 30-50 mbar for 14 to 24 hours.

Yield: 48.0 g (82.9%) colorless substance

Smp.: 171° C.

analysis:

Melting point 2-Tolperisone 3-Tolperisone 4-Tolperisone Piperidine OtherImpurities 4-MPP 171° C. <0.05% 0.16% 98.9% <0.05% <0.05% <0.05%

EXAMPLE 3 Industrial Production of Tolperisone Hydrochloride

75 kg piperidine hydrochloride and 105 kg 4-methylpropiophenone areheated to 90° C. with 180 kg of 1,3-dioxolane and 12 kg of hydrochloricacid under a nitrogen atmosphere for 7 to 20 hours. With addition of 500kg of ethyl acetate and 440 kg MTBE at a temperature in the range of(40-80° C.), a suspension of the product is produced. After that thesolid is separated from the liquid as a damp product and then dried at60-80° C. in the vacuum oven (200-500 mbar) over a period of 12-24 hourswhereby 140 kg (81.5%) of colorless crystals are isolated.

MP: 170° C.

Analysis:

Melting point 2-Tolperisone 3-Tolperisone 4-Tolperisone Piperidine OtherImpurities 4-MPP 170° C. 0.47% 0.36% 97.8% 0.9% <0.05% <0.05%

EXAMPLE 4 Industrial Recrystallization of Tolperisone Hydrochloride

60 kg of tolperisone (from example 3) are heated up in 410 kg of2-Butanone and 71 kg of isopropanol under nitrogen atmosphere and underreflux. After an optional hot filtration, by cooling a suspension of theproduct results. After that the solid is separated from the liquid as adamp product and then dried at 60-80° C. in the vacuum oven (200-500mbar) over a period of 12-24 hours whereby 45 kg (75%) of colorlesscrystals are isolated.

mp.: 173° C.

Analysis:

Melting point 2-Tolperisone 3-Tolperisone 4-Tolperisone Piperidine OtherImpurities 4-MPP 173° C. <0.05% 0.14% 98.5% <0.05% <0.05% <0.05%

EXAMPLE 5 Industrial Production of Tolperisone Hydrochloride

107 kg of piperidine hydrochloride and 150 kg of 4-methylpropionphenoneare heated up to 90° C. with 159 kg of 1,3-dioxolane and 107 L ofhydrochloric acid under a nitrogen atmosphere for 7 to 20 hours. Withaddition of 783 kg ethyl acetate and 322 kg of methyl tert-butylether ata temperature of (40-80° C.), a suspension of the product is produced.After separating the liquid, the damp product is dried at 60-80° C. inthe vacuum oven (200-500 mbar) for a period of 12-24 hours, whereby 200kg (81.5%) colorless crystals are isolated.

mp.: 170° C.

EXAMPLE 6 Industrial Recrystallization of Tolperisone Hydrochloride

190 kg of tolperisone (from example 5) in 1300 kg of 2-butanone and 224kg isopropanol are heated under nitrogen atmosphere and refluxed. Afteran optimal hot filtration, by cooling a suspension of the product isproduced. After separating the liquid, the damp product is dried at60-80° C. in the vacuum oven (200-500 mbar) for a period of 12-24 hours,whereby 143 kg (75%) colorless crystals are isolated.

mp.: 173° C.

In summary, an example of the invention can be represented as follows:

A method is described for manufacturing an acid addition salt of2,4′-dimethyl-3-piperidinopropiophenone (tolperisone) with apharmaceutical acceptable acid, of the formula

by reacting 4-methylpropiophenone with piperidine hydrochloride and1,2-dioxolane in the presence of an acid as catalyst and the resultingtolperisone as an acid addition salt is filtered off after cooling ofthe reaction mixture.

1. Method for manufacturing pharmaceutically acceptable acid additionsalts of 2,4′-dimethyl-3-piperidinopropiophenone (tolperisone), offormula (A)

said acid addition salts having a formula (B)

characterized by the fact that 4-methylpropiophenone of the formula

is reacted with piperidine hydrochloride of the formula

and 1,2-dioxolane of the formula

in presence of an acid serving as a catalyst, and the tolperisoneobtained in the form of an acid addition salt is separated by filteringafter the reaction mixture has cooled down.
 2. Method according to claim1, characterized by the fact that the reaction is carried out in thepresence of catalytic quantities of an acid, in particular aqueoushydrochloric acid.
 3. Method according to claims 1 or 2, characterizedby the fact that the reaction is carried out in a solvent.
 4. Methodaccording to claim 3, characterized by the fact that the reaction ispreferably accomplished in 1,2-dioxolane as a solvent in a concentrationrange from 1 to 6 preferably 3.6 mol/lit.
 5. Method according to claims1 to 4, characterized by the fact that the resulting tolperisone withthe inorganic acid, such as hydrochloric acid is converted, into theaddition salt.
 6. Method according to claims 1 to 5, characterized bythe fact that tolperisone is isolated as an addition salt by addition tothe reaction mixture of at least a solvent, such as ethyl acetate andmethyl tert-butyl-ether.